Acroleins a-substituted

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. 87 Cycloaddition of sodium ( >3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

Two other applications of catalyst 364, i.e. in cycloaddition reactions of a-substituted acroleins with dienes 374 and 376, have been depicted in equations 110 and 111237. Cycloadducts 375 and 377 have been used as precursors in the syntheses of cassiol and gibberellic acid, respectively. The use of catalysts 364 and 369b in cycloadditions with acrolein resulted in low enantioselectivities with opposite face selectivities. 

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

In particular, the reduced steric bulk around the catalytic nitrogen has allowed for expansion of the scope of these reactions to more hindered substrates such as a-substituted acroleins and, importantly, a,P-unsaturated ketones, augmenting the chemistry described in Sect. 2 of this report (Fig. 14). 

Fig. 14 Activation of a-substituted acroleins using primary and secondary amines...

BINOL-catalysed enantioselective 1,3-dipolar cycloaddition between a-substituted acroleins and alkyl diazoacetates yielded chiral 2-pyrazolines with 95% ee. This methodology has been used to synthesise manzacidin A.86... 

Discussion Taddol-catalyzed DA reactions provide simple and direct routes to functionalized cyclohexenones in enantiomerically enriched form. As with the HDA reactions, the best results were obtained when pure diene and dienophile were used, and the reaction temperature was rigorously maintained. Traces of moisture or acid impact negatively upon diene stability and product enantio-purities. One important advantage of the method is the commercial availability of both taddol catalyst 119 and the diene. The best substrates for the taddol-catalyzed DA reactions were a-substituted acroleins. This reactivity profile is complementary to that found for the secondary amine-based organocatalysis developed by MacMillan and co-workers, in which -substituted acroleins provided the best results [116]. 

To a solution of catalyst (0.08 mmol) and pentafluorobenzenesulfonic acid (0.22 mmol) in nitroethane (0.125 mL) or THF (0.25 mL) was added the diene (1.6 mmol). After stirring at 0 °C or r.t., a-substituted acrolein (0.8 mmol) was added in one portion. Upon consumption of a-substituted acrolein, the reaction was quenched with saturated aqueous NaHCC>3, and the reaction mixture was diluted with pentane and washed successively with H2O and brine. The organic layer was dried (MgS04), filtered, and concentrated under reduced pressure. Purification of the Diels-Alder adduct was accomplished by silica gel chromatography, eluting with pentane ether. 

Claisen rearrangement. Allyl allenyl ethers resulting from isomerization of allyl propargyl ethers with t-BuOK are ready to undergo Claisen rearrangement. A route to a-substituted acroleins is established. 

It is evident that the condensation of aniline with a substituted acrolein to yield quinoline involves the loss not only of water but of two hydrogen atoms as well. Therefore, the illustrative mechanism is proposed here for the reaction between a simple aniline and acrolein using iodine as an oxidizing reagent. 

Recently, the group extended this methodology to a-substituted acroleins and applied their reaction nicely to the short synthesis of various enantio-enriched y-butyrolactone natural products [35aj. 

Very recendy, Luo and co-workers [18] developed a chiral primary amine 4/TfOH catalyzed Friedel-Crafts alkylation of indoles with a-substituted acroleins to generate stereocenters a to the carbonyl group via asymmetric protonation (Scheme 9.4). High enantioselectivities of the products were observed when brine was used as additives. 

Diazoalkanes have also been widely utilized in 1,3-DC reactions with various olefins to construct pyrazolines and pyrazoles, which are easily converted to various types of nitrogen-containing molecules. Maruoka and coworkers developed the unprecedented enantioselective 1,3-DC of diazoacetates 46 and a-substituted acroleins 45 by using certain chiral titanium BINOLate Lewis acids as catalysts (Scheme 2.13) [24], Furthermore, Sibi evaluated a,p-unsaturated pyrazolidinone... 

Kano, T., Hashimoto, T., Maruoka, K. (2006). Enantioselective 1,3-dipolar cycloaddition reaction between diazoacetates and a-substituted acroleins total synthesis of manzacidin A. Journal of the American Chemical Society, 128, 2174-2175. 

Subsequently, Maruoka group developed an enantioselective 1,3-dipolar cycloaddition reaction between diazoacetates and a-substituted acroleins (Scheme 1.20) [24d]. The reactions of 1.5 equivalent of ethyl or tert-butyl diazoacetate and various a-substituted acrolein derivatives afford chiral 2-pyrazolines with high... 

In comparison with the widespread application of chiral secondary amines in organocatalytic Diels-Alder reactions, only a few successful examples have been reported with the use of chiral primary amines. In the case of a-substituted acroleins, it is difficult for chiral secondary amines to activate this type of substrates, probably because of poor generation of the corresponding iminium ions. To solve this problem, Ishihara and Nakano designed and synthesized a novel class of primary amine catalysts (55) [24]. Indeed, this type of less bulky ligand proved to be effective for enantioselective Diels-Alder reactions of a-acyloxyacroleins 51 or a-phthalimidoacroleins 53 to produce the desired cycloadducts 52 or 54 with quaternary stereocenters (Scheme 38.16). 

Figure 38.2 Binaphthyl-based diamine catalysts for Diels-Alder reactions a-substituted acroleins (Scheme 38.16).

It was difficult to activate a-branched aldehydes such as acroleins with secondary amines because of the steric effect of poor generation of the corresponding iminium ions. An enantioselective Diels-Alder reaction with a-substituted acroleins 124 was realized by a primary amine organocatalyst 125 (Scheme 1.45) [68]. Acyclic dienes... 

SCHEME 145 Diels-Alder reaction with a-substituted acroleins. 

For the diazoacetates, Mamoka and coworkers reported on the chiral titanium BINOLate-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions between diazoacetates and monodentate a-substituted acroleins, which give 2-pyrazolines with an asymmetric tetrasubstituted carbon center in 2006 (Table 7.6) [23], The titanium BINOLates, such as (5)-BlNOL/Ti(OPr )4 (2 1 molar ratio) complex (TB-b) and bis (5)-binaphthoxy)(isopropoxy)titanium oxide (TB-c), showed good results in terms of yields and enantiose-lectivities compared with simple (5)-BINOL/Ti(OPr )4 (1 1 molar ratio) complex (TB-a). The synthetic utility of the present reaction was further demonstrated by the total synthesis of a bromopyrrole alkaloid manzacidin A (Scheme 7.13), which was isolated firom the Okinawan sponge Hymeniacidon sp. [24],... 

Reactions were performed with a-substituted acroleins (l.Ommol) and diazoacetate (1.5mmol) in the presence of a chiral titanium catalyst in CH2CI2. isolated yield. 

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